New chiral proline-based catalysts for silicon and zirconium oxides-promoted asymmetric Biginelli reaction

Article abstract of DOI:10.1007/s10593-018-2285-z

[Figure not available: see fulltext.] 4-Hydroxy-(2S)-prolines bearing 3,4-dihydro-2H-1,4-benzoxazine or 1,2,3,4-tetrahydroquinoline fragments were synthesized and studied as chiral catalysts in the Biginelli reaction. The target product ethyl 6-methyl-2-o

Full text of DOI:10.1007/s10593-018-2285-z

DOI 10.1007/s10593-018-2285-z
Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
New chiral proline-based catalysts for silicon and zirconium
oxides-promoted asymmetric Biginelli reaction
Yulia A. Titova1*, Dmitry A. Gruzdev1, Olga V. Fedorova1, Olga A. Alisienok2,
Anna N. Murashkevich2, Victor P. Krasnov1, Gennady L. Rusinov1,3, Valery N. Charushin1,3
1 Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 S. Kovalevskoi / Akademicheskaya St., Yekaterinburg 620990, Russia; е-mail: titova@ios.uran.ru
2 Belarusian State Technical University,
13a Sverdlova St., Minsk 220006, Belarus; e-mail: alisiyonak@belstu.by
3 Ural Federal University named after the First President of Russia B. N. Yeltsin,
28 Mira St., Yekaterinburg 620002, Russia; e-mail: rusinov@ios.uran.ru
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 417–427
Submitted December 12, 2017
Accepted January 16, 2018
4-Hydroxy-(2S)-prolines bearing 3,4-dihydro-2H-1,4-benzoxazine or 1,2,3,4-tetrahydroquinoline fragments were synthesized and studied
as chiral catalysts in the Biginelli reaction. The target product ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
was obtained with 54% enantiomeric excess (ee). An increase in ee values of the reaction product up to 76% was observed in the pres-
ence of nanosized oxides SiO2–ZrO2 as heterogeneous promoters.
Keywords: hydroxyproline, silica oxide, zirconium oxide, asymmetric catalysis, Biginelli reaction, nanosized oxide.
4-Aryl-substituted dihydropyrimidines (DHPMs), the
products of multicomponent Biginelli reaction, are well
known as cardiotropic,1 hypotensive, antitumor,2 anti-
inflammatory,3 antifungal,4 and antiviral agents,5a as well
as antioxidants.5b It is known that the pharmacological
activity of enantiomers of chiral DHPMs can vary consi-
derably. For example, the (R)-enantiomer of compound
SQ-32926 (Fig. 1) exhibits 400 times higher hypotensive
activity than the (S)-enantiomer.2a The (S)-enantiomer of
L-771668 is considerably more active against the benign
prostate hyperplasia than the (R)-enantiomer.6 The inhibitory
activity of (S)-monastrol against mitotic kinesin Eg5 is
15 times higher than that of (R)-monastrol.7 Therefore,
development of new approaches to enantiomerically pure
(or enantiomerically enriched) DHPMs through the
Biginelli reaction (Scheme 1) is a challenging task for
organic synthesis.
Asymmetric homogeneous catalysis currently plays a
leading role in solving this problem. A variety of organic
compounds, such as BINOL and quinine derivatives,
proline-derived chiral amines, and metal complexes of
Figure 1. Structures of some biologically active DHPMs.
chiral ligands have been reported to act as chiral catalysts
in the Biginelli reaction.8 As a rule, one, two, or more
homogeneous organic additives (acids, amines, salts) are
used in combination with a chiral catalyst. These additives
are designed to increase chemoselectivity of the reaction,
0009-3122/18/54(4)-0417©2018 Springer Science+Business Media, LLC
417

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
Scheme 1
H
N
O
R
HO
2a–g
Me
N
Me
N
O
Me
N
Me
Me
HN
R =
O
2c
F
and, at the same time, to assist a chiral catalyst to enhance
the enantiomeric excess of the product. We have demon-
strated that application of nanosized metal oxides as hetero-
geneous promoters in combination with chiral catalysts is a
new approach which allows to increase a stereocatalytic
activity of the latter. In particular, the combined use of
nanooxides (Al2O3, NiO, and MgO) and chiral catalysts
((S)-proline, quinine sulfate) made it possible to increase an
enantiomeric excess of dihydropyrimidinone (S)-1 derived
from the three-component Biginelli reaction (Scheme 1)
from 0 to 23%.9 The ee values of dihydropyrimidinone
(R)-1 were increased from 39 to 52% and yield from 29 to
82% when the synthesis was carried out in the presence of
well-recognized chiral catalyst (2S,4R)-4-hydroxyprolyl-
(S)-1-phenylethylamine 2a10 (Fig. 2) and nanosized oxides
SiO2–ZrO2.11 It should be noted that nanosized oxides are
easily accessible and recyclable heterogeneous promoters,12
that increases their economic attractivity.
The derivatives of proline and 4-hydroxyproline occupy
an important position among chiral catalysts of the
Biginelli reaction.8 Relatively simple structure and
availability in optically pure form make this family of
chiral compounds attractive for the development of new
catalytic systems. In particular, effective catalysts for the
asymmetric Biginelli reaction include (2S,4R)-4-hydroxy-
proline amides bearing bulky alkyl or aryl substituents.10c
In this respect, it is of interest to prepare new chiral
catalysts for the stereoselective Biginelli reaction based on
optically pure heterocyclic amines. Methyl derivatives of
3,4-dihydro-2H-1,4-benzoxazine and 1,2,3,4-tetrahydro-
quinoline have been chosen as conformationally rigid com-
pounds bearing aromatic fragments capable of π–π inter-
actions. Also it is worth mentioning that some derivatives
of dihydrobenzoxazines and tetrahydroquinolines have
already been used as chiral ligands for catalytic stereo-
selective reactions, such as addition of allylamines to
indoles,13 reduction of acrylates, aminoacrylates,14 and
β-keto esters,15 as well as the Heck reaction.16
2b
2d
F
2a
HN
i-Bu
HN
i-Bu
O
O
N
Me
N
Me
N
O
2e
NH
2f
NH
2g
NH
HO
F
HO
O
O
N
Me
N
Me
N
Me
O
F
O
2j
F
F
2i
2h
Figure 2. (S)-Proline-derived chiral catalysts.
In this communication, we wish to report on the synthe-
sis of a new family of (S)-proline derivatives bearing frag-
ments of chiral heterocyclic amines, such as 3-methyl-3,4-
dihydro-2H-1,4-benzoxazine and 2-methyl-1,2,3,4-tetrahydro-
quinoline (Fig. 2), and their use as chiral catalysts for the
synthesis of dihydropyrimidinone 1 in the presence of nano-
sized oxides of metals and silicon. We also studied the effect of
the structure of a chiral catalyst, the nature of nanooxide
promoters and organic additives as well as the effect of the reac-
tion temperature on the stereochemical outcome of the reaction.
(2S,4R)-4-Hydroxyproline-based chiral catalysts 2b–g and
their analogs 2h–j were synthesized either from enantio-
pure amines (S)-3a–c and (R)-3c17a–c (Scheme 2) or from
diastereoisomerically pure amides (S,S)-5a and (S,S)-5b
obtained via acylative kinetic resolution of racemic amines
3a–c (Scheme 3).17b,d
To obtain catalysts 2b–e, we carried out the acylation of
corresponding enantiopure amines (S)-3a–c and (R)-3c
with (3R,5S)-5-chlorocarbonyl-1-(trifluoroacetyl)pyrrolidin-
3-yl trifluoroacetate (4)18 followed by the alkaline hydro-
lysis of protecting groups (Scheme 2). Acylation in the
Scheme 2
418

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
Boc
N
Scheme 3
OH
1''
Boc
5''
N
HOOC
2''
4'' OH
7
O
NH2NH2·H2O
DIPEA, TBTU
CH2Cl2
O
O
O
3''
TFA, CH2Cl2
rt, 4 h
EtOH
2f
(77%)
NH
2'
NPhth
i-Bu
NH2
i-Bu
N
N
X
N
2g (72%)
rt, 24 h
, 1 h
X
i-Bu
X
Me
8a X = CH2 (84%)
8b
Me
Me
(S,S)-5a X = CH2
(S,S)-6a X = CH2 (83%)
5b
6b
(S,S)- X = O (95%)
(S,S)- X = O
X = O (87%)
Scheme 4
presence of a weakly basic and weakly nucleophilic tertiary
amine (PhNEt2) was not accompanied by epimerization,
and compounds 2b–e were obtained in diastereomerically
pure form (according to NMR data). Moreover, recently it
has been found that the amide bearing the moiety of chiral
heterocyclic amine 3a is not prone to epimerization under
basic conditions.19
followed by hydrogenolysis of the resulting amide (S,S)-11
(Scheme 5). Amide (S,S)-11 was obtained with de 99.2%
(according to HPLC data when compared with a mixture of
diastereomers of compound 11 obtained from racemic
amine 3a).
Scheme 5
The use of acyl chloride 4 in the amidation reaction
allowed us to obtain the target compounds 2b–e in high
yields (72–99%). At the same time, all attempts to prepare
the corresponding amides from N-Boc- or N-Cbz-protected
4-hydroxyprolines in the presence of such coupling agents
as DCC, EDC, TBTU, and CDI failed. A low reactivity of
amines (S)-3a–c is likely to be explained by some steric
hindrances and low nucleophilicity of the arylamino group.
Removal of the phthaloyl group in amides (S,S)-5a,b by
hydrazinolysis resulted in amines (S,S)-6a,b in 83–95%
yields (Scheme 3).
Since some chiral diamines are well-recognized stereo-
selective organocatalysts,25 we attempted to reduce the
carbonyl group in compounds 2b,d to obtain corresponding
tertiary diamines.
Reduction of amide 2d under the action of LiAlH4 in
THF similar to the known procedure26 resulted in diamine
2j in moderate yield (Scheme 6). However, the reaction of
amide 2b with LiAlH4 under the same conditions led to the
C–N bond break. As a result, amino compound (S)-3a was
isolated from the reaction mixture in 52% yield.
Coupling of compounds (S,S)-6a,b to (2S,4R)-N-Boc-
4-hydroxyproline (7) in the presence of TBTU followed by
treatment of the resulting compounds 8a,b with trifluoro-
acetic acid (TFA) afforded the target catalysts 2f,g.
Compound 2h having the opposite to 2b configuration
of the chiral center in the hydroxyproline residue was
obtained from (2S,4R)-N-Cbz-4-hydroxyproline by the intra-
molecular Mitsunobu reaction20 followed by aminolysis of
bicyclic lactone (S,S)-9 and removal of the Cbz-protecting
group in compound 10 by hydrogenolysis (Scheme 4).
It is known that opening of the lactam ring in compound
(S,S)-9 or its analogs derived from (2S,4R)-4-hydroxy-
proline under the action of alcohols,21 the azide ion,22 or an
aqueous LiOH23 leads to the corresponding derivatives of
(2S,4S)-4-hydroxyproline. However, due to a low nucleo-
philicity and steric hindrances, amine (S)-3a poorly reacts
with compound (S,S)-9 in refluxing toluene. A prolonged
heating of reactants in the presence of a catalytic amount of
p-toluenesulfonic acid (a similar procedure was used in a
reported method24) resulted in amide 10 in low yield (11%).
The (S)-proline-based chiral catalyst 2i was obtained by
the acylation of (S)-7,8-difluoro-3,4-dihydro-3-methyl-2H-
1,4-benzoxazine ((S)-3a) with N-Cbz-(S)-prolyl chloride
Scheme 6
419

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
Table 1. Screening of chiral catalysts 2b–j
the presence of the carbonyl group, the structure of amide
substituent, and the presence and configuration of the
hydroxy group in the pyrrolidine ring. Thus, replacement of
the quinoline fragment in catalyst for benzoxazine and
difluorobenzoxazine moieties resulted in a lower enantio-
meric excess of compound 1 (Table 1, cf. entries 3, 4 and 1, 2).
Reduction of the C=O group into CH2 (compound 2j)
resulted in some decrease in the product ee, but did not
affect its yield (entries 3 and 10). Changing the hydroxy
group configuration from (R) to (S) in position 4 of the
pyrrolidine ring (compounds 2b,h) led to inversion of the
configuration of the chiral center in compound 1 (entries 1
and 8). It is worth noting that an increase in the content of
(S)-enantiomer 1 is observed when catalyst 2i does not
have the hydroxy group in the pyrrolidine ring (entry 9 vs
entry 8). As it follows from Table 1 (entries 3 and 5),
(S)-configuration of the methyl group in position 2 of tetra-
hydroquinoline 2d is preferable for the formation of
(R)-enantiomer 1. Use of catalysts 2f,g with isobutyl
substituent afforded dihydropyrimidine 1 with ee 32 and
38%, respectively (entries 6 and 7). Catalyst 2d was the
most stereoselective in the studied reaction (ee 54%).
As mentioned above, the use of homogeneous additives
of different nature (acids, amines, salts) in reaction mixtures
containing chiral catalysts is a conventional technique for
enhancing stereo- and chemoselectivity of the Biginelli
reaction.8b Based on the literature data,27 we applied the
most effective homogeneous additives for the proline-derived
chiral catalyst 2d (Table 2). Indeed, in the presence of
TFA, o-nitrobenzoic acid (o-NBA), and tert-BuNH2·TFA,
we managed to increase insignificantly the yield of com-
pound 1 with retention of the stereoselectivity (Table 2,
entries 1, 4, 6).
(10 mol % of chiral catalyst, THF, rt, 45 h)
in the synthesis of compound 1
Compound 1
Yield, %
Entry
Chiral catalyst
ее, %
10 (R)
18 (R)
54 (R)
53 (R)
40 (R)
32 (R)
38 (R)
18 (S)
47 (S)
35 (R)
1
2
19
26
13
15
7
2b
2c
3
2d
4
2d (60 h)
5
2e
2f
6
18
13
29
16
12
7
2g
2h
2i
8
9
10
2j
Compounds 2b–j were examined as chiral catalysts for
the asymmetric synthesis of ethyl 6-methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) (Scheme 1)
in THF at room temperature. The data is presented in Table 1.
1
Based on the H NMR spectra of the reaction mixtures,
it has been shown that the synthesis of dihydropyrimi-
dinone 1 in the presence of catalysts 2b–j in THF at 23°C
takes place predominantly through the formation of imine
12 derived from interaction of urea with aldehyde (Scheme 7),
as it was described before.12 In this case, benzaldehyde
interacts with acetoacetic ester to form the Knoevenagel
product 13 that does not react with urea under these
reaction conditions and is accumulated in the reaction
mixture as a by-product. The formation of compound 13
fell down to 1–4% when the following order of reagent
loading was used: at first benzaldehyde, urea, and a chiral
catalyst were mixed followed by the addition of acetoacetic
ester to the reaction mixture in 30 min. It has been found
that besides product 1 and intermediate 13, only starting
materials are observed in the reaction mixture after 45 h.
Increasing the reaction time up to 60 h did not result in an
increase in the conversion of the starting reagents (Table 1,
entry 4).
We examined nanosized mixed oxides SiO2–ZrO2 with
various Si–Zr ratios (1:1, 2:1, and 4:1) as well as single
oxides SiO2 and ZrO2 as heterogeneous promoters in
combination with chiral catalyst 2d.
Nanooxides SiO2 and ZrO2 inhibited the reaction, which
was reflected in lower yields of the target product 1,
however, they did not change the enantioselectivity of the
process (Table 3). There was even an increase in the ee
value from 54 to 68% in the presence of SiO2. Yields of
compound 1 and the content of its (R)-enantiomer
increased in the presence of mixed nanooxides SiO2–ZrO2
with growing content of SiO2. This can possibly be
Scheme 7
EtO2C
Me
O
O
H2N
NH2
O
N
NH2
12
Table 2. Effects of additives
(10 mol % of compound 2d, THF, rt, 45 h)
Ph
Ph
EtO2C
Me
PhCHO
NH
Compound 1
Homogeneous additive
Entry
O
EtO2C
Yield, %
eе, %
58
52
14
55
60
58
–
N
H
O
Ph
H2N
NH2
1
2
3
4
5
6
7
TFA
2-Chloro-4-nitrobenzoic acid
p-TSA
23
19
27
21
5
EtO2C
Me
1
Me
O
O
13
o-NBA
It has been established that activity of chiral catalysts 2b–j
in the asymmetric synthesis of compound 1 varies, and the
values of enantiomeric excess proved to be dependent
significantly on the structure of a chiral catalyst, including
tert-BuNH2·p-TSA
tert-BuNH2·TFA
Piperidine·p-TSA
15
<1
420

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
Table 3. Results and scope of the asymmetric Biginelli reaction
Scheme 8
O
in the presence of nanooxides
N
Ph
M
O
(10 mol % of compound 2d, 10 mol % of oxide,
10 mol % of additive, THF, rt, 45 h)
N H
H
+
H
PhCHO
O
M
H2N
NH2
Reaction
Compound 1
O
Nanooxide
–
Additive
tempe-
12
Yield,% eе, %
rature, °С
–
23
23
23
23
23
18
40
23
18
12
18
18
18
13
5
54
68
54
56
63
70
58
63
76
29
30
66
68
SiO2
ZrO2
–
HO
O
H
O
M
–
3
OEt
Ph
N
SiO2–ZrO2 (Si–Zr, 1:1)
SiO2–ZrO2 (Si–Zr, 2:1)
SiO2–ZrO2 (Si–Zr, 2:1)
SiO2–ZrO2 (Si–Zr, 4:1)
SiO2–ZrO2 (Si–Zr, 4:1)
SiO2–ZrO2 (Si–Zr, 4:1)
SiO2–ZrO2 (Si–Zr, 4:1)
SiO2–ZrO2 (Si–Zr, 4:1)
SiO2–ZrO2 (Si–Zr, 4:1)
–
8
O
NH
–
17
15
10
18
15
6
Me
O
M
O
O
N
–
O
M
OEt
N H
H
Me
–
O
M
H
HO
O
–
–
HO
Me
Ph
–
EtO2C
Me
O
MxOy
NH
N
H
TFA
о-NBA
20
8
O
N
H
OEt
O
SiO2–ZrO2 (Si–Zr, 4:1) tert-BuNH2·TFA
17
1
explained by a growth of the specific area of nanooxide
surface as well as a significant increase of concentration
and strength of Brønsted and Lewis acidic sites on the
surface of mixed oxides SiO2–ZrO2 due to the presence of
the Si–O–Zr bonds.28
The presence of nanooxides SiO2–ZrO2 (Si–Zr, 4:1) in
the reaction mixture made it possible to increase ee of
dihydropyrimidinone 1 from 54 to 63%. In this case, yield
of the reaction product was increased from 3–5 to 18% due
to a more acidic character of SiO2–ZrO2 in comparison
with single oxides.
It is obvious that heterogeneous promoters (nanooxides
SiO2–ZrO2) have a stronger effect on stereocatalytic acti-
vity of chiral catalysts than homogeneous additives (acids
and salts).
It has been found that decreasing the temperature from
23 to 18°C in the reaction carried out in the presence of
catalyst 2d and SiO2–ZrO2 leads to a lower reaction rate
with simultaneous increase in the enantioselectivity (Table 3).
Further decreasing temperature down to 12°C as well as its
increase up to 40°C deteriorates both yields and ee of
compound 1 (Table 3).
No synergetic effect of nanooxides SiO2–ZrO2 and
additives (TFA or o-NBA or tert-BuNH2·TFA) was
observed. In contrast, the addition of homogeneous
additive to SiO2–ZrO2 resulted in a lower efficiency of
heterogeneous promoter, as indicated by decrease of the ee
of compound 1 from 76 to 30–68% (Table 3).
The role of nanooxide promoter in the Biginelli reaction
mechanism in the presence of catalysts 2b–j is shown in
Scheme 8. In our earlier investigation, we suggested that
probably the redistribution of electronic density occurs in
the intermediate molecules of the Biginelli reaction due to
their sorption on the active surface sites of nanooxide.9,29
This leads to a change in reactivity of the intermediates. On
the other hand, chiral inductors 2b–j do not interact with
the surface of oxide catalyst. No changes in the IR spectra
of chiral inductors 2c–f,h after their sorption on the surface
of nanosized SiO2–ZrO2 are in agreement with this
assumption.
In view of the experimental data presented in Table 1,
we propose the formation of a transition state between
catalyst 2d, ethyl acetoacetate, and N-acylimine 12 (Fig. 3).
In this transition state, ethyl acetoacetate forms bond with
nitrogen atom of the pyrrole,30 the hydrogen bonding
occurring between the hydrogen of the pyrrolic hydroxy
group and the ethoxy group of ethyl acetoacetate. The two
aromatic rings (phenyl ring of catalyst 2d and phenyl ring
of N-acylimine) may be involved in π–π interactions.
The enamine intermediate attacks the Si-face of
N-acylimine that affords (R)-enantiomer of compound 1 as
the major product. As we reported previously,11 apparently,
the key role of nanooxide promoter in the asymmetric
reaction consists in the development of additional steric
control in the reaction transition state (Fig. 3).
In conclusion, new chiral catalysts for the stereo-
selective Biginelli reaction have been obtained from
4-hydroxyproline and the optically pure methyl derivatives
of 3,4-dihydro-2H-1,4-benzoxazine and 1,2,3,4-tetrahydro-
Me
O
O M
O
M
Me
N
H
O
N
O
O
O
Et
OH
H
N
O
O
H
H
M
M
O
O
M
Figure 3. Proposed transition state for the asymmetric Biginelli
reaction in the presence of nanooxide (M–O) and catalyst 2d.
421

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
quinoline. Use of these catalysts enabled us to obtain ethyl
fluoroacetyl)oxy]proline (2.31 g, 7.13 mmol) in CH2Cl2
(25 ml) at –10°C with stirring. The reaction mixture was
stirred at −10°C for 30 min, at room temperature for 2.5 h
and then evaporated to dryness under reduced pressure.
The residue was dissolved in toluene (20 ml) and added to
a solution of the corresponding amine (S)-3a–c or (R)-3c
(6.42 mmol), N,N-diethylaniline (1.06 g, 7.13 mmol) in
toluene (30 ml). The reaction mixture was refluxed for 12 h
and then evaporated to dryness under reduced pressure.
The residue was treated with a mixture of acetone (30 ml)
and 1 M NaOH (30 ml) under stirring for 4 h at room
temperature, then evaporated to a half volume and
extracted with CHCl3 (3×25 ml). Organic layers were dried
over Na2SO4 and evaporated to dryness under reduced
pressure. The residue was purified by flash column chromato-
graphy (eluent CHCl3–MeOH, gradient from 8:2 to 1:1).
[(3S)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benz-
oxazin-4-yl][(2S,4R)-4-hydroxypyrrolidin-2-yl]methanone
(2b). Yield 1.65 g (86%), yellowish amorphous solid,
[α]D20 +66.2 (с 1.0, CHCl3). 1H NMR spectrum (DMSO-d6,
100°C), δ, ppm (J, Hz): 1.14 (3H, dd, J = 6.9, J = 0.5,
3-CH3); 1.74 (1H, dddd, J = 13.0, J = 7.4, J = 2.6, J = 0.9,
3'-CHB); 2.02 (1H, ddd, J = 13.0, J = 7.3, J = 6.0, 3'-CHA);
2.64 (1H, ddd, J = 11.5, J = 2.9, J = 0.9, 5'-CHB); 3.01 (1H,
dd, J = 11.5, J = 5.0, 5'-CHA); 2.80–3.20 (2H, m, NH, OH);
4.18 (1H, ddd, J = 10.9, J = 2.9, J = 0.5, 2-CHB); 4.24 (1H,
dd, J = 7.4, J = 7.3, 2'-CH); 4.27 (1H, dddd, J = 6.0,
J = 5.0, J = 2.9, J = 2.6, 4'-CH); 4.36 (1H, dd, J = 10.9,
J = 1.5, 2-CHA); 4.88 (1H, qdd, J = 6.9, J = 2.9, J = 1.5,
3-CH); 6.86 (1H, ddd, J = 10.1, J = 9.5, J = 8.2, H-6); 7.64
(1H, ddd, J = 9.5, J = 5.5, J = 2.5, H-5). 13C NMR
spectrum (CDCl3, 25°C), δ, ppm (J, Hz): 15.4 (br. s); 40.0;
42.9–47.2 (m); 55.2; 57.3; 70.4 (br. s); 72.7; 107.7 (d,
J = 18.3); 119.2; 120.5; 136.8 (br. s); 140.0 (dd, J = 247.3,
J = 4.7); 147.2–149.8 (m); 171.6 (br. s). Found, m/z:
299.1205 [M+H]+. C14H17F2N2O3. Calculated, m/z: 299.1207.
[(2S,4R)-4-Hydroxypyrrolidin-2-yl][(3S)-3-methyl-
6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylate with good enantiomeric excess, up to 54%, while
exploiting nanosized mixed oxides SiO2–ZrO2 made it
possible to increase ee of the Biginelli product up to 76%.
Experimental
IR spectra were recorded on a Spectrum One FT-IR
spectrometer with a diffuse reflection attachment (DRA).
1H NMR spectra were recorded on a Bruker Avance 500
(500 MHz) spectrometer, 13C and 19F NMR spectra were
recorded on a Bruker Avance 500 spectrometer (125 and
470 MHz, respectively). TMS was used as internal standard
1
for H and 13C nuclei, hexafluorobenzene for 19F nuclei.
The HRMS spectra were registered on a Bruker maXis
Impact HD instrument operating in positive ion mode with
atmospheric pressure chemical ionization (compounds
2c,h, 10), electrospray ionization (other compounds), N2
flow rate 4 l/min, nebulizer pressure 0.4 bar, probe voltage
4.5 kV. Elemental analysis was performed using a
PerkinElmer 2400 II analyzer. Melting points were
obtained on Boetius or SMP3 (Barloworld Scientific, UK)
apparatus. Optical rotations were measured on
a
PerkinElmer 341 polarimeter. The RP-HPLC determination
of enantiomeric excess of compound 1 was performed on
an Agilent 1200 Series instrument using an YMC-Pack
Chiral-NEA-R column (250 × 4.6 mm, 5 mm); detection at
254 nm, flow rate 1.0 ml/min; eluent MeCN–H2O, 35:65.
Assignment of chromatographic peaks for both enantio-
mers of compound 1 was performed based on the published
data.31 Retention time of (S)-enantiomer was 13.86 min;
(R)-enantiomer – 16.63 min. The HPLC determination of
de of amide 11 was performed on a Knauer Smartline-1100
instrument using a ReproSil 100 Si column (250 × 4.6 mm,
5 mm); detection at 220 nm, flow rate 1.0 ml/min; eluent
n-hexane–i-PrOH, 20:1. Flash column chromatography was
performed using Silica gel 60 (230–400 mesh) (Alfa Aesar,
UK). The specific surface of SiO2 and ZrO2 was deter-
mined by the BET method using a NOVA 2000 instrument
(Quantachrome, Germany).
3,4-dihydro-4H-1,4-benzoxazin-4-yl]methanone
(2c).
Yield 1.40 g (75%), colorless amorphous solid, [α]D20 +104
1
(с 0.85, CHCl3). H NMR spectrum (DMSO-d6, 100°C),
(S)-7,8-Difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine
δ, ppm (J, Hz): 1.12 (3H, d, J = 6.8, 3-CH3); 1.71 (1H, ddd,
J = 12.9, J = 7.5, J = 2.5, 3'-CHB); 1.97 (1H, ddd, J = 12.9,
J = 7.5, J = 6.3, 3'-CHA); 2.63 (1H, ddd, J = 11.4, J = 3.0,
J = 0.8, 5'-CHB); 3.06 (1H, dd, J = 11.4, J = 5.1, 5'-CHA);
2.80–3.30 (2H, m, NH, OH); 4.11 (1H, dd, J = 10.9,
J = 2.9, 2-CHB); 4.18 (1H, dd, J = 10.9, J = 1.7, 2-CHA);
4.24–4.28 (2H, m, 2',4'-CH); 4.82 (1H, qdd, J = 6.8,
J = 2.9, J = 1.7, 3-CH); 6.84–6.87 (2H, m, H-6,8); 7.02
(1H, ddd, J = 8.2, J = 7.2, J = 1.6, H-7); 7.73–7.76 (1H, m,
H-5). 13C NMR spectrum (DMSO-d6, 25°C), δ, ppm: 15.2;
39.5 (overlapped by DMSO-d6 signal); 45.0 (br. s); 55.2;
57.2; 69.4; 71.6; 116.3; 120.0; 123.6; 124.8; 125.2; 145.5;
171.4. Found, m/z: 263.1392 [M+H]+. C14H19N2O3.
Calculated, m/z: 263.1390.
((S)-3a),17a
(RS)-7,8-difluoro-3-methyl-3,4-dihydro-2H-
1,4-benzoxazine ((RS)-3a),32 (S)-3-methyl-3,4-dihydro-2H-
1,4-benzoxazine ((S)-3b),17b (S)-2-methyl-1,2,3,4-tetra-
hydroquinoline ((S)-3c),17b (R)-2-methyl-1,2,3,4-tetrahydro-
quinoline ((R)-3c),17c (2S,2'S)-2-methyl-1-(N'-phthaloyl-
leucyl)-1,2,3,4-tetrahydroquinoline ((S,S)-5a),17d (3S,2'S)-
3,4-dihydro-3-methyl-4-(N'-phthaloylleucyl)-2H-1,4-benz-
oxazine ((S,S)-5b),17b (2S,4R)-N-trifluoroacetyl-4-[(trifluoro-
acetyl)oxy]proline,18 (2S,4R)-N-Boc-4-hydroxyproline (7),33
benzyl
(1S,4S)-3-oxo-5-oxa-5-azabicyclo[2.2.1]heptane-
5-carboxylate ((S,S)-9),20 and N-Cbz-(S)-prolyl chloride34
were obtained according to literature procedures. Other
reagents were commercially available. The solvents were
purified according to traditional methods and were used
freshly distilled.
[(2S,4R)-(4-Hydroxypyrrolidin-2-yl)][(2S)-2-methyl-
3,4-dihydroquinolin-1(2H)-yl]methanone (2d). Yield
20
Synthesis of catalysts 2b–e (General method). Oxalyl
chloride (0.93 ml, 10.7 mmol) and DMF (20 ml) were
added to a solution of (2S,4R)-1-trifluoroacetyl-4-[(tri-
1.65 g (99%), yellowish oil, [α]D +230 (с 0.95, CHCl3).
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
1.02 (3H, d, J = 6.5, 2-CH3); 1.29–1.36 (1H, m, 3-CHB);
422

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
1.40 (1H, ddd, J = 12.9, J = 7.5, J = 2.1, 3'-CHB); 1.66 (1H,
7.15 (1H, m, H-6); 7.18–7.21 (2H, m, H-5,7); 7.32–7.34
(1H, m, H-8). Found, m/z: 261.1962 [M+H]+. C16H25N2O.
Calculated, m/z: 261.1961.
ddd, J = 12.9, J = 7.9, J = 6.2, 3'-CHA); 2.29 (1H, dddd,
J = 13.1, J = 7.4, J = 5.6, J = 5.6, 3-CHA); 2.46 (1H, ddd,
J = 15.2, J = 9.6, J = 5.6, 4-CHB); 2.56 (1H, dd, J = 11.6,
J = 2.8, 5'-CHB); 2.64 (1H, ddd, J = 15.2, J = 5.6, J = 5.5,
4-CHA); 3.11 (1H, dd, J = 11.6, J = 5.2, 5'-CHA); 4.15–4.18
(2H, m, 2',4'-CH); 3.80–4.42 (2H, m, NH, OH); 4.70 (1H,
ddq, J = 7.4, J = 6.6, J = 6.5, 2-CH); 7.13 (1H, ddd, J = 7.4,
J = 7.2, J = 1.4, H-6); 7.18–7.21 (2H, m, H-5,7); 7.38 (1H,
dd, J = 7.6, J = 1.4, H-8). 13C NMR spectrum (DMSO-d6,
25°C), δ, ppm: 20.2; 25.5; 32.4; 39.5 (overlapped by
DMSO-d6 signal); 48.0; 55.4; 57.0; 71.5; 125.5; 125.7;
126.4; 127.4; 135.8 (br. s); 136.7; 172.8. Found, m/z:
261.1596 [M+H]+. C15H21N2O2. Calculated, m/z: 261.1598.
[(2S,4R)-(4-Hydroxypyrrolidin-2-yl)][(2R)-2-methyl-
3,4-dihydroquinolin-1(2H)-yl]methanone (2e). Yield
1.20 g (72%), colorless solid, mp 148–150°C (hexane–
(2S)-2-Amino-4-methyl-1-[(3S)-3-methyl-2,3-dihydro-
4H-1,4-benzoxazin-4-yl]pentan-1-one ((S,S)-6b). Yield
20
1.25 g (95%), yellowish oil, [α]D +235 (с 1.02, CHCl3).
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
0.71–0.74 (6H, m, CH3); 1.10 (3H, d, J = 6.9, 3-CH3); 1.24
(1H, ddd, J = 13.5, J = 7.1, J = 6.8, 3'-CHB); 1.42 (1H, ddd,
J = 13.5, J = 6.7, J = 6.5, 3'-CHA); 1.55–1.63 (1H, m,
4'-CH); 1.67 (2H, br. s, NH2); 3.93 (1H, dd, J = 7.1,
J = 6.5, 2'-CH); 4.06 (1H, dd, J = 10.9, J = 1.7, 2-CHB);
4.19 (1H, dd, J = 10.9, J = 3.0, 2-CHA); 4.83 (1H, qdd,
J = 6.9, J = 3.0, J = 1.7, 3-CH); 6.86–6.89 (2H, m, H-7,8);
7.04 (1H, ddd, J = 8.3, J = 7.2, J = 1.6, H-6); 7.56 (1H, dd,
J = 8.3, J = 1.1, H-5). 13C NMR spectrum (DMSO-d6,
25°C), δ, ppm: 15.0; 22.2; 22.4; 24.4; 43.0 (br. s); 45.4;
49.5; 66.9; 116.3; 120.0; 123.4; 125.1; 125.6; 145.8; 174.6.
Found, m/z: 263.1755 [M+H]+. C15H23N2O2. Calculated, m/z:
263.1754.
20
CH2Cl2), [α]D –309 (с 0.5, CHCl3). 1H NMR spectrum
(DMSO-d6, 100°C), δ, ppm (J, Hz): 1.03 (3H, d, J = 6.5,
2-CH3); 1.35–1.43 (1H, m, 3-CHB); 1.87–2.01 (2H, m,
3'-CH2); 2.26 (1H, dddd, J = 13.1, J = 6.6, J = 6.5, J = 6.0,
3-CHA); 2.48–2.55 (2H, m, 4-CHB, 5'-CHB, overlapped by
DMSO-d6 signal); 2.66 (1H, ddd, J = 15.3, J = 6.0, J = 5.9,
4-CHA); 3.10 (1H, dd, J = 11.4, J = 5.2, 5'-CHA); 4.02 (1H,
t, J = 7.6, 2'-CH); 4.25 (1H, ddt, J = 6.1, J = 5.8, J = 2.9,
4'-CH); 4.07–4.47 (2H, m, NH, OH); 4.68 (1H, ddq,
J = 6.6, J = 6.6, J = 6.5, 2-CH); 7.09–7.14 (1H, m, H-6);
7.16–7.20 (2H, m, H-5,7); 7.26 (1H, d, J = 7.8, H-8).
13C NMR spectrum (DMSO-d6, 25°C), δ, ppm: 19.6; 24.8;
31.3; 40.9; 47.7; 55.6; 57.0; 71.7; 125.4 (2C); 126.0; 127.6;
134.9 (br. s); 136.4; 172.7. Found, %: C 67.99; H 7.64;
N 10.62. C15H20N2O2·0.25H2O. Calculated, %: C 68.03;
H 7.80; N 10.58. Found, m/z: 261.1596 [M+H]+. C15H21N2O2.
Calculated, m/z: 261.1598.
Synthesis of compounds 8a,b (General method). TBTU
(1.22 g, 3.80 mmol) was added to a solution of compound
(S,S)-6a or (S,S)-6b (3.80 mmol), (2S,4R)-N-Boc-
4-hydroxyproline (7) (0.88 g, 3.80 mmol), and DIPEA
(1.98 ml, 11.4 mmol) in CH2Cl2 (35 ml). The reaction
mixture was stirred at room temperature for 24 h and then
washed with 10% aqueous citric acid (3×30 ml), saturated
aqueous NaCl (2×30 ml), 5% Na2CO3 (3×25 ml), and water
(2×20 ml). Organic layer was dried over Na2SO4 and
evaporated to dryness under reduced pressure. The residue
was purified by flash column chromatography (eluent
CHCl3–MeOH, gradient from 49:1 to 9:1).
tert-Butyl (2S,4R)-4-hydroxy-2-{[(S)-4-methyl-1-[(S)-
2-methyl-3,4-dihydroquinolin-1(2H)-yl]-1-oxopentan-2-yl]-
carbamoyl}pyrrolidine-1-carboxylate ((S,S)-8a). Yield
Synthesis of compounds 6a,b (General method). 64%
Aqueous hydrazine (0.416 ml, 8.57 mmol) was added to a
solution of compound (S,S)-5a or (S,S)-5b (4.76 mmol) in
EtOH (30 ml). The reaction mixture was refluxed for 1 h
and evaporated to dryness under reduced pressure. The
residue was treated with 2 N HCl (30 ml), the resulting
precipitate was filtered off. Filtrate was made alkaline with
Na2CO3 to pH 8 and then with NaOH to pH 12–13 and then
extracted with CHCl3 (3×20 ml). Combined organic layers
were dried over NaOH and evaporated to dryness under
reduced pressure. The residue was purified by flash column
chromatography (eluent CHCl3–MeOH, 9:1).
20
1.52 g (84%), colorless foam, [α]D +133 (с 1.0, CHCl3).
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
0.45 (3H, d, J = 6.5, CH3); 0.60 (3H, d, J = 6.5, CH3); 1.02
(3H, d, J = 6.5, 2-CH3); 1.07 (1H, ddd, J = 13.4, J = 8.2,
J = 5.0, 3'-CHB); 1.24–1.30 (1H, m, 3-CHB); 1.34 (1H, ddd,
J = 13.4, J = 9.0, J = 5.1, 3'-CHA); 1.37 (9H, s, C(CH3)3);
1.39–1.44 (1H, m, 4'-CH); 1.95–1.99 (1H, m, 3''-CHB);
2.04–2.09 (1H, m, 3''-CHA); 2.31 (1H, dddd, J = 13.0,
J = 7.7, J = 5.3, J = 5.1, 3-CHA); 2.41 (1H, ddd, J = 15.0,
J = 10.2, J = 5.3, 4-CHB); 2.65 (1H, ddd, J = 15.0, J = 5.1,
J = 5.0, 4-CHA); 3.27 (1H, ddd, J = 11.0, J = 3.2, J = 1.0,
5''-CHB); 3.45 (1H, dd, J = 11.0, J = 5.0, 5''-CHA); 4.24–
4.30 (2H, m, 2'',4''-CH); 4.62–4.69 (2H, m, 2-CH, OH);
5.01 (1H, m, 2'-CH); 7.15 (1H, ddd, J = 7.4, J = 7.4, J = 1.2,
H-6); 7.19–7.23 (2H, m, H-5,7); 7.46 (1H, d, J = 7.7, H-8);
7.53 (1H, d, J = 7.7, NH). 13C NMR spectrum (DMSO-d6,
25°C), δ, ppm (conformers A and B, ratio 7:3): 20.4 (A and
B); 20.8 (A); 21.0 (B); 22.5 (A and B); 24.0 (A and B);
25.7 (A and B); 27.8 (A); 28.1 (B); 32.7 (A and B); 38.2
(B); 39.5 (overlapped by DMSO-d6 signal, A); 41.0 (A and
B); 48.2 (A); 48.3 (B); 48.4 (A and B); 54.6 (A); 54.8 (B);
58.0 (B); 58.4 (A); 67.7 (A); 68.4 (B); 78.4 (A); 78.5 (B);
125.8 (A and B); 125.9 (B); 126.0 (A); 126.3 (A); 126.4
(B); 127.3 (A and B); 136.1 (br. s, A and B); 136.6 (A and
(2S)-2-Amino-4-methyl-1-[(2S)-2-methyl-3,4-dihydro-
quinolin-1(2H)-yl]pentan-1-one ((S,S)-6a). Yield 1.03 g
20
(83%), colorless amorphous solid, [α]D +330 (с 0.96,
1
CHCl3). H NMR spectrum (DMSO-d6, 100°C), δ, ppm
(J, Hz): 0.52 (3H, d, J = 6.6, CH3); 0.57 (3H, d, J = 6.7,
CH3); 1.03 (3H, d, J = 6.5, 2-CH3); 1.08 (1H, ddd, J = 13.4,
J = 7.5, J = 6.6, 3'-CHB); 1.17 (1H, ddd, J = 13.4, J = 7.0,
J = 6.1, 3'-CHA); 1.25–1.32 (1H, m, 3-CHB); 1.42–1.49
(1H, m, 4'-CH); 1.63 (2H, br. s, NH2); 2.30 (1H, dddd,
J = 13.0, J = 7.4, J = 5.4, J = 5.1, 3-CHA); 2.40 (1H, ddd,
J = 15.1, J = 10.1, J = 5.4, 4-CHB); 2.64 (1H, ddd, J = 15.1,
J = 5.1, J = 5.1, 4-CHA); 3.80 (1H, dd, J = 7.5, J = 6.1,
2'-CH); 4.67 (1H, ddq, J = 7.4, J = 6.8, J = 6.5, 2-CH); 7.11–
423

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
B); 153.5 (A); 153.8 (B); 171.8 (A); 172.0 (B); 172.6 (A
Leu). 13C NMR spectrum (DMSO-d6, 25°C), δ, ppm: 20.4;
22.1; 22.5; 24.1; 25.7; 32.7; 39.5 (overlapped by DMSO-d6
signal); 41.7; 47.4; 48.6; 54.9; 59.1; 71.1; 125.9 (2C);
126.0; 126.5; 127.4; 136.3; 171.6; 173.7. Found, m/z:
374.2438 [M+H]+. C21H32N3O3. Calculated, m/z: 374.2438.
(2S,4R)-4-Hydroxy-N-{4-methyl-1-[(S)-3-methyl-2,3-
dihydro-4H-1,4-benzoxazin-4-yl]-1-oxopentan-2-yl}-
pyrrolidine-2-carboxamide (2g). Yield 270 mg (72%),
and B). Found, %: C 65.64; H 8.20; N 8.74. C26H39N3O5.
Calculated, %: C 65.94; H 8.30; N 8.87.
tert-Butyl (2S,4R)-4-hydroxy-2-{[(S)-4-methyl-1-[(S)-
3-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl]-1-oxopentan-
2-yl]carbamoyl}pyrrolidine-1-carboxylate
((S,S)-8b).
20
Yield 1.57 g (87%), colorless foam, [α]D +64.5 (с 0.9,
1
CHCl3). H NMR spectrum (DMSO-d6, 100°C), δ, ppm
20
(J, Hz): 0.69 (3H, d, J = 6.5, CH3); 0.75 (3H, d, J = 6.6,
CH3); 1.10 (3H, d, J = 6.9, 3-CH3); 1.37 (9H, s, C(CH3)3);
1.37–1.42 (1H, m, 3'-CHB); 1.47–1.52 (1H, m, 3'-CHA);
1.53–1.61 (1H, m, 4'-CH); 1.89–1.94 (1H, m, 3''-CHB);
2.04 (1H, ddd, J = 12.2, J = 8.0, J = 4.1, 3''-CHA); 3.26
(1H, ddd, J = 11.0, J = 3.1, J = 1.2, 5''-CHB); 3.44 (1H, dd,
J = 11.0, J = 4.9, 5''-CHA); 4.05 (1H, dd, J = 11.0, J = 3.0,
2-CHB); 4.20 (1H, dd, J = 11.0, J = 1.7, 2-CHA); 4.22–4.26
(1H, m, 4''-CH); 4.29 (1H, dd, J = 8.0, J = 6.8, 2''-CH);
4.85 (1H, qdd, J = 6.9, J = 3.0, J = 1.7, 3-CH); 4.63 (1H, d,
J = 4.0, OH); 5.02–5.06 (1H, m, 2'-CH); 6.86–6.89 (2H, m,
H-7,8); 7.06 (1H, ddd, J = 8.2, J = 7.3, J = 1.5, H-6); 7.66–
7.68 (1H, m, H-5); 7.78 (1H, d, J = 7.3, NH). 13C NMR
spectrum (DMSO-d6, 25°C), δ, ppm (conformers A и B,
ratio 7:3): 14.8 (br. s, A and B); 22.5 (A and B); 22.6 (A
and B); 24.1 (A and B); 27.8 (A); 28.1 (B); 38.2 (B); 38.3
(B); 39.5 (overlapped by DMSO-d6 signal, A and B); 40.8
(A and B); 43.2 (br. s, A); 46.6 (br. s, B); 48.1 (A and B);
54.6 (A); 54.9 (B); 58.0 (B); 58.2 (A); 67.7 (A); 68.4 (B);
69.8 (br. s, A and B); 116.4 (A and B); 120.0 (A and B);
123.1 (A and B); 125.2 (A and B); 126.3 (A and B); 146.1
(A and B); 153.4 (A); 153.7 (B); 171.6 (br. s, A and B);
172.3 (B); 172.9 (A). Found, %: C 63.11; H 8.09; N 8.75.
C25H37N3O6. Calculated, %: C 63.14; H 7.84; N 8.84.
Synthesis of compounds 2f,g (General method).
A solution of compound (S,S)-8a or (S,S)-8b (1.01 mmol)
in a CH2Cl2–TFA mixture (1:1) (9 ml) was stirred at room
temperature for 4 h, and then evaporated to dryness under
reduced pressure. The residue was dissolved in water
(25 ml), alkalized with NaOH, and extracted with CHCl3
(3 × 15 ml). Organic layers were dried over Na2SO4 and
evaporated to dryness under reduced pressure. The residue
was purified by flash column chromatography (SiO2, eluent
CHCl3–MeOH, gradient from 19:1 to 9:1).
colorless amorphous solid, [α]D +123 (с 0.94, CHCl3).
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
0.70 (3H, d, J = 6.4, CH3); 0.75 (3H, d, J = 6.5, CH3); 1.10
(3H, d, J = 6.9, 3-CH3); 1.36–1.53 (3H, m, 3'-CH2, 4'-CH);
1.75 (1H, ddd, J = 13.1, J = 7.7, J = 5.4, 3''-CHB); 1.95
(1H, dddd, J = 13.1, J = 8.4, J = 2.6, J = 1.5, 3''-CHA); 2.78
(1H, ddd, J = 11.4, J = 2.5, J = 1.5, 5''-CHB); 2.83 (1H, dd,
J = 11.4, J = 4.2, 5''-CHA); 2.97–3.16 (1H, m, NH Pro);
3.76–3.79 (1H, m, 2''-CH); 4.06 (1H, dd, J = 11.0, J = 3.1,
2-CHB); 4.18 (1H, br. s, 4''-CH); 4.19 (1H, dd, J = 11.0,
J = 1.7, 2-CHB); 4.30 (1H, br. s, OH); 4.86 (1H, qdd,
J = 6.9, J = 3.1, J = 1.7, 3-CH); 5.07–5.11 (1H, m, 2'-CH);
7.06–7.09 (1H, m, H-6); 6.87–6.91 (2H, m, H-7,8); 7.61–
7.63 (1H, m, H-5); 7.98 (1H, d, J = 8.2, NH Leu).
13C NMR spectrum (DMSO-d6, 25°C), δ, ppm: 14.9; 21.5;
22.5; 24.4; 39.5 (overlapped by DMSO-d6 signal); 41.5;
43.4 (br. s); 47.4; 55.0; 59.0; 69.8; 71.2; 116.5; 120.2;
122.9; 125.2; 126.4; 146.1; 171.3; 174.2. Found, m/z:
376.2234 [M+H]+. C20H30N3O4. Calculated, m/z: 376.2231.
Benzyl (2S,4S)-2-[(S)-7,8-difluoro-3-methyl-3,4-dihydro-
2H-1,4-benzoxazine-4-carbonyl]-4-hydroxypyrrolidine-
1-carboxylate (10). A solution of compound (S,S)-9
(0.70 g, 2.82 mmol), amine (S)-3a (0.57 g, 3.10 mmol), and
p-TSA monohydrate (0.07 g, 0.36 mmol) in toluene (8 ml)
was refluxed for 35 h, then washed with 4 N HCl (3×7 ml),
saturated aqueous NaCl (3×7 ml), 5% aqueous NaHCO3
(3×7 ml), and water (2×7 ml). Organic layer was dried over
MgSO4 and evaporated to dryness under reduces pressure.
The residue was subjected to flash column chromatography
(eluent PhH–EtOAc) and triturated with hexane. Yield
20
130 mg (11%), yellowish oil, [α]D +167 (с 0.5, CHCl3).
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
1.09–1.14 (3H, m, 3-CH3); 1.74 (1H, ddd, J = 12.2, J = 6.1,
J = 5.9, 3'-CHB); 2.33–2.40 (1H, m, 3'-CHA); 3.26 (1H, dd,
J = 10.6, J = 5.7, 5'-CHB); 3.71 (1H, dd, J = 10.6, J = 6.3,
5'-CHA); 4.20–4.38 (3H, m, 2-CH2, 4'-CH); 4.81 (2H, br. s,
3-CH, OH); 4.96 (1H, dd, J = 8.7, J = 5.9, 2'-CH); 5.04
(2H, br. s, CH2 Cbz); 6.82–6.88 (1H, m, H-6); 7.23–7.33
(5H, m, H Ph); 7.50 (1H, br. s, H-5). 13C NMR spectrum
(DMSO-d6, 25°C), δ, ppm (conformers A and B, ratio
55:45): 15.1 (br. s, A and B); 37.9 (A); 38.4 (B); 45.5 (br. s, A
and B); 53.6 (A); 53.8 (B); 55.9 (A); 56.0 (B); 66.0 (A);
66.3 (B); 67.7 (B); 68.5 (A); 69.6 (B); 70.0 (A); 107.1 (br. s, A
and B); 119.6–120.0 (m, A and B); 121.0–121.2 (m, A and
B); 127.3 (A); 127.5 (B); 127.8 (B); 128.1 (A and B);
128.4 (A); 136.4 (B); 135.8 (A); 138.9 (dm, J = 243.1, A
and B); 146.8 (dm, J = 244.7, A and B); 153.4 (B); 154.1
(A); 170.7 (B); 171.0 (A). 19F NMR spectrum (DMSO-d6,
100°C), δ, ppm: 2.1–2.2 (1F, m, F-8); 20.8–21.1 (1F, m, F-
7). Found, m/z: 433.1570 [M+H]+. C22H23F2N2O5.
Calculated, m/z: 433.1570.
(2S,4R)-4-Hydroxy-N-{4-methyl-1-[(S)-2-methyl-3,4-di-
hydroquinolin-1(2H)-yl]-1-oxopentan-2-yl}pyrrolidine-
2-carboxamide (2f). Yield 290 mg (77%), colorless
20
1
amorphous solid, [α]D +169 (с 0.75, CHCl3). H NMR
spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz): 0.47 (3H, d,
J = 6.5, CH3); 0.59 (3H, d, J = 6.5, CH3); 1.02 (3H, d,
J = 6.5, 2-CH3); 1.08 (1H, ddd, J = 13.0, J = 8.1, J = 4.7,
3'-CHB); 1.24–1.37 (3H, m, 3-CHB, 3'-CHA, 4'-СН); 1.75
(1H, ddd, J = 13.0, J = 7.6, J = 5.4, 3''-CHB); 1.94–2.00
(1H, m, 3''-CHA); 2.31 (1H, dddd, J = 13.0, J = 7.7, J = 5.2,
J = 5.1, 3-CHA); 2.41 (1H, ddd, J = 15.4, J = 10.2, J = 5.2,
4-CHB); 2.65 (1H, ddd, J = 15.4, J = 5.1, J = 5.0, 4-CHA);
2.77–2.84 (2H, m, 5''-CH2); 3.78–3.81 (1H, m, 2''-CH);
3.30–4.00 (1H, m, NH Pro); 4.16–4.19 (1H, m, 4''-CH);
4.32 (1H, s, OH); 4.63–4.69 (1H, m, 2-CH); 5.03–5.07
(1H, m, 2'-CH); 7.15–7.18 (1H, m, H-6); 7.21–7.24 (2H, m,
H-5,7); 7.39 (1H, d, J = 7.8, H-8); 7.93 (1H, d, J = 8.3, NH
424

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
[(3S)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benz-
δ, ppm: 0.98–1.15 (3H, m); 1.79–1.89 (1.5H, m); 1.92–2.03
(1.5H, m); 2.12–2.20 (0.5H, m); 2.30–2.39 (0.5 H, m); 3.46–
3.54 (2H, m); 4.03–4.45 (2H, br. m); 4.60–5.10 (4H, br. m);
6.82–6.88 (1H, m); 7.15–7.35 (5H, m); 7.37–7.57 (1H, m).
19F NMR spectrum (DMSO-d6, 100°C), δ, ppm: 2.1–2.2
(0.5F, m); 2.2–2.4 (0.5F, m); 20.6–21.1 (1F, m). Found, %:
C 63.20; H 5.57; F 8.79; N 6.57. C22H22F2N2O4.
Calculated, %: C 63.45; H 5.33; F 9.12; N 6.73.
oxazin-4-yl][(2S,4S)-4-hydroxypyrrolidin-2-yl]methanone
(2h). A mixture of compound 10 (0.104 g, 0.24 mmol) and
10% Pd/C (10.4 mg) in MeOH (4 ml) was autoclaved
(10 atm H2) at room temperature for 2 h, then filtered off
and evaporated to dryness under reduced pressure. The
residue was purified by flash column chromatography
(eluent CHCl3–MeOH, gradient from 9:1 to 6:4). Yield
20
130 mg (80%), brown oil, [α]D +103 (с 1.0, CHCl3).
[(3S)-7,8-Difluoro-3-methyl-2,3-dihydro-4H-1,4-benz-
oxazin-4-yl][(2S)-pyrrolidin-2-yl]methanone (2i). A mixture
of compound 11 (1.04 g, 2.5 mmol) and 10% Pd/C (0.1 g)
in MeOH (10 ml) was autoclaved (10 atm H2) at room
temperature for 2 h, filtered, and evaporated to dryness
under reduced pressure. The residue was purified by flash
column chromatography (eluent CHCl3–MeOH, 1:1). Yield
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
1.14 (3H, d, J = 6.9, 3-CH3); 1.69–1.73 (1H, m, 3'-CHB);
2.14 (1H, ddd, J = 13.2, J = 8.8, J = 6.1, 3'-CHA); 2.79 (1H,
dd, J = 11.4, J = 4.8, 5'-CHB); 2.85 (1H, dd, J = 11.4,
J = 2.8, 5'-CHA); 2.97 (1H, br. s, NH, overlapped by water
signal); 4.12–4.15 (1H, m, 2'-CH); 4.18–4.22 (2H, m,
2-CHB, 4'-CH); 4.34 (1H, dd, J = 10.9, J = 1.4, 2-CHA);
4.28–4.52 (1H, m, OH); 4.82 (1H, qdd, J = 6.9, J = 2.8,
J = 1.4, 3-CH); 6.84–6.89 (1H, m, H-6); 7.59 (1H, ddd,
J = 9.4, J = 5.5, J = 2.5, H-5). 13C NMR spectrum (DMSO-d6,
25°C), δ, ppm (J, Hz): 15.0; 39.5 (overlapped by DMSO-d6
signal); 44.8 (br. s); 54.9; 57.7; 69. 9; 70.8; 106.9 (d,
J = 17.5); 119.7 (d, J = 3.4); 121.3; 136.1 (dd, J = 9.6,
J = 2.0); 138.9 (dd, J = 243.6, J = 5.4); 146.7 (d,
J = 241.4); 171.4. 19F NMR spectrum (DMSO-d6, 100°C),
δ, ppm: 1.9–2.0 (1F, m, F-8); 20.7–21.8 (1F, m, F-7).
Found, m/z: 299.1204 [M+H]+. C14H17F2N2O3. Calculated,
m/z: 299.1202.
20
0.672 g (96%), yellowish oil, [α]D +68.9 (с 1.0, CHCl3).
1H NMR spectrum (DMSO-d6, 100°C), δ, ppm (J, Hz):
1.15 (3H, d, J = 6.9, 3-CH3); 1.65–1.89 (4H, m, 3',4'-CH2);
2.77 (1H, ddd, J = 10.5, J = 7.2, J = 6.2, 5'-CHB); 2.96 (1H,
ddd, J = 10.5, J = 6.6, J = 6.6, 5'-CHA); 2.90–3.06 (1H, m,
NH); 4.09 (1H, dd, J = 7.9, J = 6.2, 2'-CH); 4.19 (1H, dd,
J = 10.9, J = 2.8, 2-CHB); 4.35 (1H, dd, J = 10.9, J = 1.2,
2-CHA); 4.85–4.90 (1H, m, 3-CH); 6.83–6.88 (1H, m,
H-6); 7.63 (1H, ddd, J = 9.4, J = 5.5, J = 2.5, H-5).
13C NMR spectrum (DMSO-d6, 25°C), δ, ppm (J, Hz):
15.1; 26.1; 29.4; 44.9 (br. s); 46.8; 58.3; 69.9; 106.8 (d,
J = 17.9); 119.6 (dd, J = 7.8, J = 4.0); 121.5; 136.0 (dd, J = 9.9,
J = 3.1); 138.9 (dd, J = 243.4, J = 5.4); 146.6 (dm,
J = 245.6); 171.8. Found, m/z: 283.1258 [M+H]+.
C14H17F2N2O2. Calculated, m/z: 283.1253.
Benzyl (S)-2-[(S)-7,8-difluoro-3-methyl-3,4-dihydro-
2H-1,4-benzoxazine-4-carbonyl]pyrrolidine-1-carboxylate
((S,S)-11). A solution of N-Cbz-(S)-prolyl chloride (0.873 g,
3.26 mmol) in toluene (14 ml) was added to a solution of
amine (S)-3a (0.6 g, 3.26 mmol) and N,N-diethylaniline
(0.486 g, 3.26 mmol) in toluene (19 ml). The reaction
mixture was kept at 50°C for 6 h then washed with 4 N
HCl (3×20 ml), saturated aqueous NaCl (3×25 ml), 5%
aqueous NaHCO3 (2×25 ml), and water (2×25 ml). Organic
layer was dried over MgSO4 and evaporated to dryness
under reduced pressure. The residue was purified by flash
column chromatography (eluent benzene–EtOAc, 9:1).
(3R,5S)-5-{[(2S)-2-methyl-3,4-dihydroquinolin-1(2H)-
yl]methyl}pyrrolidin-3-ol (2j). A solution of compound
2d (0.385 g, 1.48 mmol) in THF (8 ml) was added
dropwise to a suspension of LiAlH4 (0.225 g, 5.92 mmol)
in THF (5 ml) under stirring at −10°C for 25 min. The
reaction mixture was stirred under reflux for 6 h, cooled to
0°C. Then 1 M NaOH (1 ml) and water (0.6 ml) were
added to the reaction mixture. Precipitate was filtered off,
filtrate was evaporated to dryness under reduced pressure.
The residue was purified by flash column chromatography
(eluent CHCl3–MeOH, 1:1). Yield 133 mg (36%), brown
20
Yield 1.08 g (80%), yellowish oil, [α]D +163 (с 0.7,
1
CHCl3), de 99.2%. HPLC: τ 7.23 min. H NMR spectrum
20
(DMSO-d6, 100°C), δ, ppm (J, Hz): 1.07–1.15 (3H, m, 3-CH3);
1.79–1.89 (2H, m, 4'-CH2); 1.93–2.03 (1H, m, 3'-CHB);
2.12–2.20 (1H, m, 3'-CHA); 3.50 (2H, t, J = 6.5, 5'-CH2);
3.70–4.45 (2H, m, 2-CH2); 4.72–4.92 (1H, m, 3-CH); 4.98
(1H, dd, J = 8.3, J = 4.1, 2'-CH); 5.05 (2H, br. s, СH2 Cbz);
6.79–6.88 (1H, m, H-6); 7.23–7.33 (5H, m, H Ph); 7.37–
7.57 (1H, m, H-5). 19F NMR spectrum (DMSO-d6, 100°C),
δ, ppm: 2.1–2.2 (1F, m, F-8); 20.7–20.9 (1F, m, F-7).
Found, %: C 63.45; H 5.53; F 8.84; N 6.48. C22H22F2N2O4.
Calculated, %: C 63.45; H 5.33; F 9.12; N 6.73.
oil, [α]D −52.8 (с 0.96, CHCl3). 1H NMR spectrum
(CDCl3, 25°C), δ, ppm (J, Hz): 1.10 (3H, d, J = 6.6,
2'-CH3); 1.67 (1H, ddd, J = 13.8, J = 8.3, J = 5.5, 4-CHB);
1.76 (1H, dddd, J = 12.4, J = 6.2, J = 3.9, J = 2.9, 3'-CHB);
1.91–1.98 (3H, m, 3'-CHA, 4-CHA, NH); 2.67 (1H, ddd,
J = 16.2, J = 5.1, J = 2.9, 4'-CHB); 2.84–2.91 (2H, m,
4'-CHA, 2-CHB); 3.04 (1H, dd, J = 14.6, J = 7.3, CH2); 3.17
(1H, dd, J = 11.7, J = 5.6, 2-CHA); 3.48 (1H, s, OH); 3.49
(1H, dd, J = 14.6, J = 6.0, CH2); 3.53–3.57 (1H, m, 5-CH);
3.73–3.79 (1H, m, 2'-CH); 4.43–4.46 (1H, m, 3-CH); 6.56–
6.59 (1H, m, H-6'); 6.62 (1H, d, J = 8.2, H-5'); 6.98 (1H, d,
J = 7.3, H-8'); 7.02–7.06 (1H, m, H-7'). 13C NMR spectrum
(CDCl3, 25°C), δ, ppm: 17.3; 23.4; 27.6; 40.1; 52.8; 53.9;
54.7; 55.2; 72.3; 110.9; 115.6; 121.7; 127.0; 129.25; 144.4.
Found, m/z: 247.1801 [M+H]+. C15H23N2O. Calculated,
m/z: 247.1805.
Benzyl 2-[7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-
benzoxazine-4-carbonyl]pyrrolidine-1-carboxylate (mixture
of diastereomers (S,S) and (R,S) in ratio 1:1) (11). The
diastereomeric mixture 11 was synthesized similarly to
compound (S,S)-11 starting from N-Cbz-(S)-prolyl chloride
(0.072 g, 0.27 mmol) and amine (RS)-3a (0.100 g, 0.54 mmol).
Yield 46 mg (41%), yellowish oil. HPLC: τ(S,S)-11 7.2 min;
Synthesis of the nanocomposites. Single oxides SiO2
1
τ(R,S)-11 12.4 min. H NMR spectrum (DMSO-d6, 100°C),
and ZrO2 were prepared by the sol-gel method.11,35 The
425

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
mixed SiO2–ZrO2 nanomaterials were obtained in a similar
3. Bozsing, D.; Sohar, P.; Gigler, G.; Kovacs, G. Eur. J. Med.
Chem. 1996, 31, 663.
way by mixing the corresponding sols in a predetermined
ratio, followed by their drying at 100–120°C until a
constant weight. Thus obtained nanooxides were amor-
phous. The specific area of their surface was determined by
the BET method: SiO2 222 m2/g, ZrO2 33 m2/g, SiO2–ZrO2
(1:1) 59 m2/g, SiO2–ZrO2 (2:1) 123 m2/g, SiO2–ZrO2 (4:1)
288 m2/g.
4. (a) Ashok, M.; Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem.
2007, 42, 380. (b) Ghorab, M. M.; Mohamed, Y. A.;
Mohamed, S. A.; Ammar, Y. A. Phosphorus, Sulfur Silicon
Relat. Elem. 1996, 108, 249.
5. (a) Shkurko, O. P.; Tolstikova, T. G.; Sedova, V. F. Russ.
Chem. Rev. 2016, 85, 1056. (b) Magerramov, A. M.;
Kurbanova, M. M.; Abdinbekova, R. T.; Rzaeva, I. A.;
Farzaliev, V. M.; Allakhverdiev, M. A. Russ. J. Appl. Chem.
2006, 79, 787. [Zh. Prikl. Khim. 2006, 79, 796.]
Ethyl
6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (1). Method I (in the presence
of nanooxides). A solution of benzaldehyde (0.050 g,
0.47 mmol), urea (0.084 g, 1.41 mmol), and appropriate
catalyst 2b–j (0.047 mmol) in THF (2 ml) was stirred for
30 min. Then ethyl acetoacetate (0.074 g, 0.70 mmol) was
added, the reaction mixture was stirred for 30 min, and an
appropriate oxide (0.047 mmol) was added. The reaction
mixture was stirred at 22–25°C for 45 h and evaporated to
dryness under reduced pressure. The residue was dissolved
in DMF, and oxide was removed by centrifugation at
14000 rpm for 6 min. The enantiomeric excess of
supernatant was analyzed by chiral RP-HPLC, then it was
evaporated to dryness under reduced pressure. The residue
was treated with Et2O (2×20 ml), then stirred with water
(10 ml) for 3 h, filtered off, and dried to yield compound 1.
Method II (in the presence of tert-BuNH2·TFA,
tert-BuNH2·p-TSA, or piperidine·p-TSA). A solution of
benzaldehyde (0.050 g, 0.47 mmol), urea (0.084 g,
1.41 mmol), catalyst 2d (0.012 g, 0.047 mmol), and
appropriate salt (0.047 mmol) in THF (2 ml) was stirred for
30 min. Then ethyl acetoacetate (0.074 g, 0.70 mmol) was
added. The reaction mixture was stirred at 22–25°C for
45 h and evaporated to dryness under reduced pressure.
The residue was dissolved in DMF and the enantiomeric
excess of supernatant was analyzed by chiral RP-HPLC.
Method III (in the presence of 2-chloro-4-nitrobenzoic
acid, TFA, p-TSA, or o-NBA). After stirring a solution of
compound 2d (0.012 g, 0.047 mmol) and the appropriate
acid (0.047 mmol) in THF (2 ml) at 22–25°C for 30 min,
benzaldehyde (0.050 g, 0.47 mmol) and urea (0.084 g,
1.41 mmol) were added, and a solution was stirred for
30 min. Then ethyl acetoacetate (0.074 g, 0.70 mmol) was
added. The further procedure was similar to method II.
Mp of compound 1 204–206°C (EtOH) (mp 203–204°C36).
Found, %: C 64.80; H 6.15; N 10.79. C14H16N2O3.
6. Kappe, C. O. In Multicomponent Reactions; Zhu, J.;
Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005, p. 109.
7. (a) DeBonis, S.; Simorre, J. P.; Crevel, I.; Lebeau, L.;
Skoufias, D. A.; Blangy, A.; Ebel, C.; Gans, P.; Cross, R.;
Hackney, D. D.; Wade, R. H.; Kozielski, F. Biochemistry
2003, 42, 338. (b) Maliga, Z.; Kapoor, T. M.; Mitchison, T. J.
Chem. Biol. 2002, 9, 989.
8. (a) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev.
2012, 41, 3969. (b) Heravi, M. M.; Asadi, S.; Lashkariani, B. M.
Mol. Diversity 2013, 17, 389. (c) Wan, J.-P.; Lin, Y.; Liu, Y.
Curr. Org. Chem. 2014, 18, 687.
9. Fedorova, O. V.; Valova, M. S.; Titova, Yu. A.;
Ovchinnikova, I. G.; Grishakov, A. N.; Uimin, M. A.;
Mysik, A. A.; Ermakov, A. E.; Rusinov, G. L.; Charushin, V. N.
Kinet. Catal. 2011, 52, 226.
10 (a) Mao, J.; Guo, J. Chirality 2010, 22, 173. (b) Watts, J.;
Luu, L.; McKee, V.; Carey, E.; Kelleher, F. Adv. Synth. Catal.
2012, 354, 1035. (c) Xin, J.; Chang, L.; Hou, Z.; Shang, D.;
Liu, X.; Feng, X. Chem.–Eur. J. 2008, 14, 3177.
(d) Yadav, G. D.; Singh, S. Tetrahedron: Asymmetry 2015,
26, 1156.
11. Krivtsov, I. V.; Titova, Yu. A.; Ilkaeva, M. V.; Avdin, V. V.;
Fedorova, O. V.; Khainakov, S. A.; Garcia, J. R.; Rusinov, G. L.;
Charushin, V. N. J. Sol–Gel Sci. Technol. 2014, 69, 448.
12. Fedorova, O. V.; Titova, Yu. A.; Vigorov, A. Yu.;
Toporova, M. S.; Alisienok, O. A.; Murashkevich, A. N.;
Krasnov, V. P.; Rusinov, G. L.; Charushin, V. N. Catal. Lett.
2016, 146, 493.
13. Liu, W.-B.; He, H.; Dai, L.-X.; You, S -L. Synthesis 2009, 2076.
14. Pullmann, T.; Engendahl, B.; Zhang, Z.; Hölscher, M.;
Zanotti-Gerosa, A.; Dyke, A.; Franciò, G.; Leitner, W.
Chem.–Eur. J. 2010, 16, 7517.
15. Kesselgruber, M.; Lotz, M.; Martin, P.; Melone, G.; Müller, M.;
Pugin, B.; Naud, F.; Spindler, F.; Thommen, M.; Zbiden, P.;
Blaser, H. U. Chem.–Asian J. 2008, 3, 1384.
16. Kündig, E. P.; Meier, P. Helv. Chim. Acta. 1999, 82, 1360.
17. (a) Charushin, V. N.; Krasnov, V. P.; Levit, G. L.;
Korolyova, M. A.; Kodess, M. I.; Chupakhin, O. N.;
Kim, M. H.; Lee, H. S.; Park, Y. J.; Kim, K. C. Tetrahedron:
Asymmetry 1999, 10, 2691. (b) Gruzdev, D. A.; Levit, G. L.;
Krasnov, V. P. Tetrahedron: Asymmetry 2012, 23, 1640.
(c) Krasnov, V. P.; Levit, G. L.; Bukrina, I. M.; Andreeva, I. N.;
Sadretdinova, L. Sh.; Korolyova, M. A.; Kodess, M. I.;
Charushin, V. N.; Chupakhin, O. N. Tetrahedron: Asymmetry
2003, 14, 1985. (d) Gruzdev, D. A.; Levit, G. L.; Kodess, M. I.;
Krasnov, V. P. Chem. Heterocycl. Compd. 2012, 48, 748.
[Khim. Geterotsikl. Soedin. 2012, 805.]
1
Calculated, %: C 64.60; H 6.20; N 10.76. H NMR spect-
rum was in full agreement with the literature data.36
The work was financially supported by the Russian
Science Foundation (14-13-01077 as a part of chiral
catalysts synthesis) and the Russian Foundation for Basic
Research (16-29-10757-ofi_m as a part of the asymmetric
Biginelli reaction study).
18. Mori, M.; Uozumi, Y.; Kimura, M.; Ban, Y. Tetrahedron
1986, 42, 3793.
References
19. Gruzdev, D. A.; Vakarov, S. A.; Levit, G. L.; Krasnov, V. P.
Chem. Heterocycl. Compd. 2014, 49, 1795. [Khim. Geterotsikl.
Soedin. 2014, 1936.]
1. (a) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug. Res.
1987, 16, 309. (b) Kappe, O. C. Tetrahedron 1993, 49, 6937.
2. (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O'Reelly, B. C. J. Med. Chem.
1991, 34, 806. (b) Kappe, O. C. Eur. J. Med. Chem. 2000, 35,
1043. (c) Triggle, D. J. Cell. Mol. Neurobiol. 2003, 23, 293.
20. Bowers-Nemia, M. M.; Joullié, M. M. Heterocycles 1983, 20, 817.
21. (a) Kronenthal, D. R.; Mueller, R. H.; Kuester, P. L.;
Kissick, T. P.; Johnson, E. J. Tetrahedron Lett. 1990, 31,
426

Chemistry of Heterocyclic Compounds 2018, 54(4), 417–427
1241. (b) Thaning, M.; Wistrand, L. G. Helv. Chim. Acta
29. (a) Titova, Yu. A.; Fedorova, O. V.; Rusinov, G. L.;
Charushin, V. N. Russ. Chem. Rev. 2015, 84, 1294.
(b) Fedorova, O. V.; Koryakova, O. V.; Valova, M. S.;
Ovchinnikova, I. G.; Titova, Y. A.; Rusinov, G. L.;
Charushin, V. N. Kinet. Catal. 2010, 51, 566.
30. Saha, S; Moorthy, J. N. J. Org. Chem. 2011, 76, 396.
31. Kleidernigg, O. P.; Kappe, O. C. Tetrahedron: Asymmetry
1997, 8, 2057.
32. Charushin, V. N.; Gorbunov, E. B.; Rusinov, G. L.;
Likholobov V. A.; Rodionov, V. A. RU Patent 2434005;
Chem. Abstr. 2011, 155, 683753.
33. Asagarasu, A.; Uchiyama, T.; Achiwa, K. Chem. Pharm. Bull.
1998, 46, 697.
34. Cassal, J.-M.; Fürst, A.; Meier, W. Helv. Chim. Acta 1976,
59, 1917.
35. (a) Murashkevich, A. N.; Lavitskaya, A. S.; Barannikova, T. I.;
Zharskiy, I. M. J. Appl. Spectr. 2008, 75, 730. [Zh. Prikl.
Spectr. 2008, 75, 724.] (b) Murashkevich, A. N.;
Alisienok, O. A.; Zharskiy, I. M.; Yukhno, E. K. J. Sol-Gel
Sci. Technol. 2013, 68, 509.
36. Liberto, N. A.; Silva, S. P.; de Fátima, A. D.; Fernandes, S. A.
Tetrahedron 2013, 69, 8245.
1986, 69, 1711.
22. (a) Gómez-Vidal, J. A.; Silverman, R. B. Org. Lett. 2001, 3,
2481. (b) Seo, J.; Martásek, P.; Roman, L. J.; Silverman, R. B.
Bioorg. Med. Chem. 2007, 15, 1928.
23. Chorghade, M. S.; Mohapatra, D. K.; Sahoo, G.; Gurjar, M. K.;
Mandlecha, M. V.; Bhoite, N.; Moghe, S.; Raines, R. T. J.
Fluorine Chem. 2008, 129, 781.
24. Shiuey, S. J.; Partridge, J. J.; Uskoković, M. R. J. Org. Chem.
1988, 53, 1040.
25. (a) Kizirian, J.-C. Chem. Rev. 2008, 108, 140. (b) Lucet, D.;
Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(c) Terakado, D.; Oriyama, T. Org. Synth. 2006, 83, 70.
26. Amedjkouh, M.; Ahlberg, P. Tetrahedron: Asymmetry 2002,
13, 2229.
27. (a) Ding, D.; Zhao, C. G. Eur. J. Org. Chem. 2010, 3802.
(b) Li, Z. Y.; Xing, H. J.; Huang, G. L.; Sun, X. Q.; Jiang, J. L.;
Wang, L. Y. Sci. China: Chem. 2011, 54, 1726.
28. (a) Tanabe, K. Solid Acids and Bases. Their Catalytic
Properties; Academic Press: New-York, London, 1970, p. 88.
(b) Valova, M. S.; Koryakova, O. V.; Maximovskikh, A. I.;
Fedorova, O. V.; Murashkevich, A. N.; Alisienok, O. A.
J. Appl. Spectrosc. 2014, 81, 422.
427